There is increasing evidence for synergism between HSV-2 and HIV-1. Mucosal HIV-1 replication is increased when HSV-2 DNA is present. This project will measure the effect of clinical and subclinical HSV-2 reactivation on mucosal and systemic HIV-1 replication, and proposes studies to evaluate if abrogation of HSV reactivation by daily of acyclovir will reduce HIV-1 replication. Specific Aim 1 randomizes HSV-2/ HIV co-infected persons into a double blind cross over study of acyclovir 800 mg BID vs. placebo. HIV-1 replication on mucosal surfaces will be evaluated during and after the 8-week treatment period. This trial involves cohorts in Seattle, Peru, & Cameroon. Recent data indicates HSV-2 reactivation is not reduced by HAART therapy. Specific Aim 2 will evaluate if acyclovir reduces viral evolution and the frequency and amount of HIV-1 RNA expressed in tissue and lymphoid reservoirs of the HIV-1/HSV-2 co-infected person. This study will enroll HAART treated patients, untreated patients with CD4 >350 cells/mm 3, and HAART failures requiring salvage therapy. Specific Aim 3 is directed at a collaboration with Dr. Susan Allen from the University of Zambia in evaluating if HSV-2 infection of the source partner reduces the transmission of HIV. It uses samples from a prospective cohort of HIV-1 discordant couples in Lusaka. Specific Aim 4 describes an international, multi-center study to evaluate whether400 mg PO BID of daily acyclovir will reduce the rate of HIV acquisition among heterosexual women and men. Investigators associated with this project planned the trial, and separate R01 funding has been obtainedf or the trialsites. The central laboratories associated with this P01 will provide centralized laboratory services to the U.S. (Seattle & New York City) and international sites (Peru, Zambia& Zimbabwe) for evaluating HSV-2 prevalent and HIV incident infection. Taken together, these studies will define whether therapy for HSV can make a significant impact on reducing acquisition/ transmission of HIV and improve the care of the HSV-2/HIV-infected person.